|Pharmacokinetic Properties and Safety Profile of Histamine Dihydrochloride Injection in Chinese Healthy Volunteers: A Phase I, Single-center, Open-label, Randomized Study|
|Li, Jiapeng1; Huang, Xiaojun2; Wang, Qian1; Jing, Shan3; Jiang, Hao2; Wei, Zhongna1; Zang, Yannan1; Liu, Yang1; Zhao, Libo1; Fang, Yi1; Feng, Wanyu1|
|关键词||Chinese Healthy Volunteers Histamine Dihydrochloride Pharmacokinetics Safety|
|WOS标题词||Science & Technology|
|类目[WOS]||Pharmacology & Pharmacy|
|研究领域[WOS]||Pharmacology & Pharmacy|
|关键词[WOS]||ACUTE MYELOID-LEUKEMIA ; POST-CONSOLIDATION IMMUNOTHERAPY ; LIQUID-CHROMATOGRAPHY ; CEREBROSPINAL-FLUID ; MASS-SPECTROMETRY ; INTERLEUKIN-2 ; CANCER ; METABOLITES ; METHYLTRANSFERASE ; RELAPSE|
Purpose: Histamine dihydrochloride (HDC) injection has been approved in Europe for the treatment of adults with acute myeloid leukemia, used in combination therapy with the T-cell-derived cytokine interleukin-2. Despite years of clinical applications of HDC in Europe, no data are available on its tolerability and pharmacokinetic properties in Chinese patients. The objective of this study was to determine the safety profile and pharmacokinetic properties of HDC in Chinese healthy volunteers (HVs).
Methods: In this Phase I, single-center, open-label, randomized study, 20 Chinese HVs were randomized to receive a single dose of 0.5 or 1.0 mg HDC via a 10-minute subcutaneous injection. Whole-blood and urine samples were collected at designated time points after dosing. Plasma and urine concentrations of histamine and metabolite N-methyl histamine were measured using a validated HPLC-MS/MS method. Pharmacokinetic parameters were estimated through noncompartmental procedures based on concentration-time data. Adverse events and evaluation of clinical laboratory tests were used to assess the safety profile. The pharmacokinetic profile for a single-dose of 1.0 mg HDC in Chinese HVs was compared with that in Western HVs.
Findings: No severe adverse events occurred in this study, and the severity of all adverse events was grade I according to the Common Terminology Criteria for Adverse Events, version 4.0. For the pharmacokinetic parameters of histamine at the 0.5-mg and 1.0-mg dose levels, t(1/2) was 0.50 and 1.02 hours; T-max was 0.15 and 0.14 hours; mean C-max was 26.59 and 71.01 nmol/L; AUC(0-t) was 8.35 and 20.43 nmol/h/L; AUC(0-infinity) was 9.61 and 22.69 nmol/h/L; accumulated amount excreted in urine within 24 hours was 125.93 and 145.52 nmol; and maximum urine excretion rates were 21.85 and 38.94 nmol/h, respectively. For N-methyl histamine at the 0.5-mg and 1.0-mg dose levels, t1/2 was 0.58 and 0.66 hours; T-max was 0.28 and 0.26 hours; mean C-max was 17.01 and 23.54 nmol/L; AUC(0-t) was 7.72 and 17.08 nmol/h/L; AUC(0-infinity) was 9.01 and 19.62 nmol/h/L; accumulated amount excreted in urine within 24 hours was 331.7 and 583.21 nmol; and maximum urine excretion rates were 53.29 and 133.53 nmol/h, respectively.
Implications: Both single-dose 0.5 mg and 1.0 mg HDC were well tolerated in Chinese HVs, and the pharmacokinetic profile of HDC in Chinese HVs was characterized in this study. A single dose of 1.0 mg HDC had a more rapid but similar extent of absorption, a wider distribution, and a little more rapid elimination in Chinese HVs compared with Western HVs. Findings from this study support additional clinical trials for HDC using in Chinese patients. (C) 2015 Elsevier HS Journals, Inc. All rights reserved.
|资助机构||Major Project of National Science and Technology "Creation of Major New Drugs" during the Twelfth Five-Year Plan Period|
|作者单位||1.Peking Univ, Peoples Hosp, Dept Pharm, Beijing 100044, Peoples R China|
2.Peking Univ, Peoples Hosp, Inst Hematol, Beijing 100871, Peoples R China
3.Peking Univ, Peoples Hosp, Drug Clin Trial Inst, Beijing, Peoples R China
|Li, Jiapeng,Huang, Xiaojun,Wang, Qian,et al. Pharmacokinetic Properties and Safety Profile of Histamine Dihydrochloride Injection in Chinese Healthy Volunteers: A Phase I, Single-center, Open-label, Randomized Study[J]. CLINICAL THERAPEUTICS,2015,37(10):2352-2364.|
|APA||Li, Jiapeng.,Huang, Xiaojun.,Wang, Qian.,Jing, Shan.,Jiang, Hao.,...&Feng, Wanyu.(2015).Pharmacokinetic Properties and Safety Profile of Histamine Dihydrochloride Injection in Chinese Healthy Volunteers: A Phase I, Single-center, Open-label, Randomized Study.CLINICAL THERAPEUTICS,37(10),2352-2364.|
|MLA||Li, Jiapeng,et al."Pharmacokinetic Properties and Safety Profile of Histamine Dihydrochloride Injection in Chinese Healthy Volunteers: A Phase I, Single-center, Open-label, Randomized Study".CLINICAL THERAPEUTICS 37.10(2015):2352-2364.|